Oral Administration Of Lipopolysaccharide Research Articles

Restoration of Spatial Learning Through Oral Administration of Lipopolysaccharides in Diabetes-related Cognitive Dysfunction.

In a previous report, our group showed that oral administration of lipopolysaccharides (LPS) from Pantoea agglomerans can prevent the progression of streptozotocin (STZ)-induced diabetes-related cognitive dysfunction (DRCD) in mice without causing significant side-effects. However, the treatment effects of oral administration of LPS to DRCD remain unknown. We modified our previous animal experimental model to investigate whether oral administration of LPS can recover cognitive function after DRCD onset. The Morris water maze (MWM) revealed a significant decrease in learning and memory abilities at 13 days after intracerebroventricular administration of STZ, thereby providing evidence of the occurrence of DRCD in the animal model. Oral administration of LPS (1 mg/kg per day) started after cognitive impairment was observed. After 28 days of treatment, mice receiving LPS via the oral route showed significant recovery of spatial learning ability, a symptom of early dementia, while only a trend toward recovery was seen for spatial memory compared to the untreated group. These results, limited to MWM, suggest that oral administration of LPS is a promising therapeutic strategy for restoring decreased spatial learning ability.

Oral route lipopolysaccharide as a potential dementia preventive agent inducing neuroprotective microglia.

In today's aging society, dementia is an urgent problem to be solved because no treatment or preventive methods have been established. This review focuses on oral administration of lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, as a novel preventive drug for dementia. LPS is also called endotoxin and is well known to induce inflammation when administered systemically. On the other hand, although we humans routinely ingest LPS derived from symbiotic bacteria of edible plants, the effect of oral administration of LPS has hardly been studied. Recently, oral administration of LPS was reported to prevent dementia by inducing neuroprotective microglia. Furthermore, it has been suggested that colony stimulating factor 1 (CSF1) is involved in the dementia prevention mechanism by oral administration of LPS. Thus, in this review, we summarized the previous studies of oral administration of LPS and discussed the predicted dementia prevention mechanism. In addition, we showed the potential of oral LPS administration as a preventive drug for dementia by highlighting research gaps and future issues for clinical application development.

Prevention of Diabetes-Associated Cognitive Dysfunction Through Oral Administration of Lipopolysaccharide Derived From Pantoea agglomerans.

Diabetes-related cognitive dysfunction (DRCD) is a serious complication induced by diabetes. However, there are currently no specific remedies for DRCD. Here, we show that streptozotocin-induced DRCD can be prevented without causing side effects through oral administration of lipopolysaccharide (LPS) derived from Pantoea agglomerans. Oral administration of LPS (OAL) prevented the cerebral cortex atrophy and tau phosphorylation induced by DRCD. Moreover, we observed that neuroprotective transformation of microglia (brain tissue-resident macrophages) is important for preventing DRCD through OAL. These findings are contrary to the general recognition of LPS as an inflammatory agent when injected systemically. Furthermore, our results strongly suggest that OAL promotes membrane-bound colony stimulating factor 1 (CSF1) expression on peripheral leukocytes, which activates the CSF1 receptor on microglia, leading to their transformation to the neuroprotective phenotype. Taken together, the present study indicates that controlling innate immune modulation through the simple and safe strategy of OAL can be an innovative prophylaxis for intractable neurological diseases such as DRCD. In a sense, for modern people living in an LPS-depleted environment, OAL is like a time machine that returns microglia to the good old LPS-abundant era.

Oral Administration of Lipopolysaccharide Prevents Cognitive Impairment in Streptozotocin-induced Diabetic Mice in a Blood Glucose-independent Manner.

Diabetes is a risk factor for dementia. However, no radical preventive method for diabetes-associated dementia has yet been developed. Our previous study revealed that oral administration of lipopolysaccharide (LPS) prevents high-fat diet-induced cognitive impairment. Therefore, we investigated here whether oral administration of LPS (OAL) could also prevent diabetes-associated dementia. Diabetic mice were produced by intraperitoneal administration of streptozotocin (STZ), and then mice were orally administered LPS. Cognitive ability was evaluated using the Morris water maze, and gene expression was analyzed in isolated microglia. OAL prevented STZ-induced diabetic cognitive impairment, but did not affect blood glucose levels. Moreover, OAL promoted the expression of neuroprotective genes in microglia, such as heat shock protein family 40 (HSP40) and chemokine CCL7. OAL prevents diabetes-associated dementia, potentially via promotion of HSP40 and CCL7 expression in microglia.

A Novel Anti-inflammatory Phenotype Transformed by Repetitive Low-dose Lipopolysaccharide in Primary Peritoneal Tissue-resident Macrophages.

Our previous studies suggested that oral administration of lipopolysaccharide (LPS) regulates the progression of various diseases via transformation of tissue-resident macrophages (MΦ). Recently, we characterized microglia transformed by repetitive low-dose LPS treatment (REPELL-microglia) in vitro, and this response was similar to that observed in response to oral administration of LPS in vivo. Here, we examined the characteristics of peritoneal tissue-resident MΦ (pMΦ) transformed by repetitive low-dose LPS treatment (REPELL-pMΦ). Primary pMΦ were treated with low-dose LPS (1 ng/ml) three times; subsequently, phagocytic activity and gene expression were evaluated. REPELL-pMΦ exhibited high phagocytic activity and elevated expression of Arg1, Gipr, Gdnf, and Fpr2. The gene expression profiles observed in REPELL-pMΦ were distinct from those of REPELL-microglia. REPELL-pMΦ have the potential to promote clearance of xenobiotics and to suppress inflammation. The present study also demonstrates the diversity of tissue-resident MΦ transformation that reflect their tissue origin.

Oral administration of lipopolysaccharides from Escherichia coli (serotype O111:B4) does not induce an effective systemic immune response in milk-fed Holstein calves

It is well established that intravenous administration of lipopolysaccharides (LPS)-cell wall components from gram-negative bacteria-induce acute inflammatory responses in dairy calves, but the effect of oral administration of LPS to dairy calves is currently unknown. To evaluate the effects of oral administration of LPS derived from Escherichia coli (serotype O111:B4) on innate immune responses in milk-fed Holstein calves, 20 visually healthy calves (34 ± 1 d) received 4 L of milk with LPS (12 μg/kg body weight; n = 10; LPS) or without LPS (n = 10; control) at the morning feeding. Samples were collected at 0.5 h before the morning feeding and at 3, 6, 24, 48, 72, and 168 h after the morning feeding to measure rectal temperature and heart rate, as well as plasma-negative and plasma-positive acute phase proteins (i.e., haptoglobin, serum amyloid A, albumin, total protein, and fibrinogen) and immunoglobulin concentrations (IgG, IgM, and IgA). None of these measurements was affected by the oral administration of LPS. Oral administration of LPS at 12 μg/kg of body weight did not induce an acute inflammatory response in visually healthy milk-fed Holstein calves when administered in milk.

389 Effects of Oral Administration of Lipopolysaccharide on Growth Performance and Immune Response of Nursery Pigs.

389 Effects of Oral Administration of Lipopolysaccharide on Growth Performance and Immune Response of Nursery Pigs.

Primed Immune Responses Triggered by Ingested Bacteria Lead to Systemic Infection Tolerance in Silkworms.

In the present study, we examined whether microorganisms collaterally ingested by insects with their food activate the innate immune system to confer systemic resistance against subsequent bacterial invasion. Silkworms orally administered heat-killed Pseudomonas aeruginosa cells showed resistance against intra-hemolymph infection by P. aeruginosa. Oral administration of peptidoglycans, cell wall components of P. aeruginosa, conferred protective effects against P. aeruginosa infection, whereas oral administration of lipopolysaccharides, bacterial surface components, did not. In silkworms orally administered heat-killed P. aeruginosa cells, P. aeruginosa growth was inhibited in the hemolymph, and mRNA amounts of the antimicrobial peptides cecropin A and moricin were increased in the hemocytes and fat body. Furthermore, the amount of paralytic peptide, an insect cytokine that activates innate immune reactions, was increased in the hemolymph of silkworms orally administered heat-killed P. aeruginosa cells. These findings suggest that insects sense bacteria present in their food by peptidoglycan recognition, which activates systemic immune reactions to defend the insects against a second round of infection.

Lyn activity protects mice from DSS colitis and regulates the production of IL-22 from innate lymphoid cells.

Intestinal homeostasis requires a complex balance of interactions between diverse resident microbial communities, the intestinal epithelium, and the underlying immune system. We show that the Lyn tyrosine kinase, a critical regulator of immune cell function and pattern-recognition receptor (PRR) responses, has a key role in controlling gastrointestinal inflammation. Lyn⁻/⁻ mice were highly susceptible to dextran sulfate sodium (DSS)-induced colitis, whereas Lyn gain-of-function (Lyn(up)) mice exhibited attenuated colitis during acute and chronic models of disease. Lyn(up) mice were hypersensitive to lipopolysaccharide (LPS), driving enhanced production of cytokines and factors associated with intestinal barrier function, including interleukin (IL)-22. Oral administration of LPS was sufficient to protect antibiotic-treated Lyn(up) but not wild-type mice from DSS, highlighting how Lyn-dependent changes in the nature/magnitude of PRR responses can impact intestinal health. Furthermore, protection from DSS-induced colitis and increased IL-22 production in response to LPS did not depend on the adaptive immune system, with increased innate lymphoid cell-derived IL-22 correlating with Lyn activity in dendritic cells. These data reveal a key role for Lyn in the regulation of innate immune responses and control of intestinal inflammation.

The effects of natural and modified clinoptilolite on intestinal barrier function and immune response to LPS in broiler chickens

The protection of intestinal barrier function and the anti-inflammatory effects of natural clinoptilolite (NCLI) and modified clinoptilolite (MCLI) were investigated in broilers that were repeatedly challenged with lipopolysaccharide (LPS). A total of 288 1-d-old broiler chicks were divided equally into three treatment groups: control, NCLI-treated (2%) and MCLI-treated (2%). Half of the birds from each treatment group were challenged with 0.9% NaCl solution or LPS (250μg/kg body weight, administered orally) at 16, 18 and 21d of age. The results indicated that, prior to LPS challenge, the diet had no effect on bird growth performance (P>0.05). The oral administration of LPS was also not associated with any significant changes in poultry performance (P>0.05). In LPS-challenged birds that were pretreated with NCLI (2%) or MCLI (2%), the LPS-induced increases in the plasma and intestinal mucosa concentrations of TNF-α, IL-1β, IL-2, IL-6, IL-4 and IL-10 were dramatically attenuated. Additionally, significant decreases in the plasma d-lactic acid and diamine oxidase (DAO) levels were found in birds that were pretreated with NCLI or MCLI. Furthermore, both NCLI and MCLI reduced the sICAM-1 concentration in the intestinal mucosa. In conclusion, NCLI and MCLI are able to prevent the LPS-induced intestinal mucosa damage and inflammatory response in vivo. These beneficial effects suggest that NCLI and MCLI act as anti-inflammatory agents in part by inhibiting neutrophil infiltration and hyperactivation and by suppressing the secretion of various plasma and intestinal mucosa inflammatory mediators.

Lipopolysaccharides stimulate adrenomedullin synthesis in intestinal epithelial cells: Release kinetics and secretion polarity

Adrenomedullin (AM), a potent vasodilator peptide initially isolated from a human pheochromocytoma, functions as an antimicrobial peptide in host defense. In this study, we investigated changes in AM levels in intestinal epithelial cells and the mechanism of its secretion and cellular polarity after exposure to lipopolysaccharides (LPS). When a rat small intestinal cell line (IEC-18 cells) was exposed to LPS, enzyme-linked immunosorbent assay revealed a dose-dependent increase in AM together with an increase in AM mRNA expression, as determined by real-time polymerase chain reaction. Up-regulation of AM by LPS was dose-dependently inhibited by LY294002, PD98059, SP600125 and calphostin-C, suggesting the involvement of the phosphatidylinositol 3 kinase, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase and protein kinase C pathways, respectively, in this process. When polarized IEC-18 cells in a Transwell chamber were stimulated with LPS, AM secretion was directed primarily toward the side of LPS administration (either the apical or basolateral side). In situ hybridization revealed that AM mRNA was expressed in epithelial cells and in the connective tissue in the lamina propria of the jejunum after intraperitoneal or oral administration of LPS. Higher levels of AM mRNA expression were observed in rats treated with LPS via the intraperitoneal route, compared with those treated via the oral route. These findings suggest that intestinal AM plays an important role in mucosal defense in the case of intestinal luminal infection, as well as in the modulation of hemodynamics in endotoxemia.

Anti-Inflammatory Effect of Buckwheat Sprouts in Lipopolysaccharide-Activated Human Colon Cancer Cells and Mice

In conducting an in vitro screening of ethanol extracts from various natural foods using a human colon cancer cell line (CoLoTC cells), an extract of buckwheat sprouts (ExtBS) was found to express significant anti-inflammatory activity. The anti-inflammatory activity of ExtBS was confirmed by oral administration of lipopolysaccharide (LPS) to mice. Inflammatory cytokines (interleukin 6 and tumor necrosis factor alpha) were markedly up-regulated in the spleen and liver from LPS-administrated mice, and combinatory treatment with LPS and ExtBS decreased up-regulation of them in both cytokines. Both serum cytokine levels corresponded to their gene expressions in tissues, but no anti-inflammatry effect in mice was observed when ExtBS was treated intraperitoneally. ExtBS oral administration also showed protective activity as to hepatic injury induced by galactosamine/LPS treatment. Based on these data, we suggest that ExtBS contains anti-inflammatory compounds.

Administration of lipopolysaccharide increases specific and non-specific immune parameters and survival in carp ( Cyprinus carpio) infected with Aeromonas hydrophila

Relative percent survival (RPS) and immunomodulating effect of lipopolysaccharide (LPS) were studied in Cyprinus carpio against the bacterial pathogen, Aeromonas hydrophila. A virulent strain of A. hydrophila was isolated from previously infected fish. LPS was extracted from the virulent A. hydrophila and characterized by SDS-PAGE analysis. Different concentrations of LPS (10, 50 and 100 µg/fish, 15, 75 and 150 µg ml − 1 , 0.1, 0.25 and 0.5%) were administered to test animals on days 1, 7 and 14 through intraperitoneal injection (i.p.), bathing and oral routes, respectively. Control and test animals were challenged with LD 50 concentration of A. hydrophila by i.p. on day 16, mortality determined and RPS calculated. Intraperitoneal injection of 50 and 100 µg of LPS/fish and 150 µg of LPS ml − 1 through bathing significantly enhanced the RPS; oral administration did not influence the RPS rate. Test animals injected with 100 µg of LPS showed significant increase in total leucocyte count and an increase in the population of monocytes and neutrophils. Superoxide anion production by kidney macrophages and secondary immune response against A. hydrophila following vaccination were also elevated. RT-PCR and northern blot analysis of interleukin-1 mRNA showed elevated expression in kidney macrophages on day 16 in fish injected with 50 and 100 µg of LPS/fish, which presumably aided efficient killing of the bacterial pathogen. However, oral administration of LPS did not protect the animals from A. hydophila infection. Classical and alternative complement pathways were not affected by LPS administration by any of the three routes. LPS administration through injection and bathing effectively stimulates the non-specific cellular as well as secondary immune response and offers protection against A. hydrophila infection in carps.

Dual effect of neutrophils on secretory component production by human bronchial epithelial cells

It is well known that intravenous administration of lipopolysaccharide (LPS) induces severe toxicity in mammals. The maximum tolerated dose of intravenous administration of LPS in humans is reported to be only 1 to 4 ng/kg body weight. However, oral administration of a high dose of LPS caused no toxicity or systemic inflammation in other mammals, birds, or fish. Two weeks of oral administration of a high dose of LPS (2 mg/kg) did not induce toxicity in a rat experiment. Moreover, several experiments have reported that oral administration of LPS had preventative and curative properties against various diseases, including allergic, and lifestyle-related diseases. These results demonstrate that mucosal administration of LPS acts via a different regulatory mechanism in biological responses from that of parenteral administration. Mucosal administration of LPS is thought to be quite promising for prevention of diseases, but LPS is rarely used. In order to expand the usage of oral administration of LPS for preventing lifestyle and allergic diseases, it will be necessary to clarify the mechanisms that arouse immune responses after oral administration of LPS. This short review presents a recent observation of the usefulness of orally administered LPS.

Reactivation of Antigen‐Induced Arthritis in Mice by Oral Administration of Lipopolysaccharide

We examined whether oral administration of lipopolysaccharide (LPS) from Escherichia coli reactivated antigen-induced arthritis (AIA) in mice that is one of models of human rheumatoid arthritis. To induce AIA, mice were immunized by subcutaneous injection of ovalbumin (OVA) emulsified with complete Freund's adjuvant into the base of the tail (day 0) followed by intraarticular injection of OVA on day 21. To investigate the ability of LPS to reactivate AIA, varying doses of LPS were p.o. administered 48 h after the challenge injection. The results showed that administration of LPS was followed by reactivation of AIA in a dose-related fashion. The reactivation of AIA by LPS was associated with increases in interferon-gamma, interleukin-1beta and tumour necrosis factor-alpha. Polymyxin B sulfate given immediately before administration of LPS suppressed the reactivation of AIA. These findings suggest that LPS from intestinal bacteria may play a role in the reactivation of joint inflammation in which immune responses to pathogenic antigens are involved.

The costs of mounting an immune response are reflected in the reproductive fitness of the mosquito Anopheles gambiae

We have used Anopheles gambiae, a major vector of malaria in Africa, to test the hypothesis that the operation of a surveillance or immune system against microorganisms and parasites can be costly to the reproductive success of the host. Blood‐fed mosquitoes were challenged with an immune elicitor, lipopolysaccharide (LPS), and their resultant antimicrobial activity, accumulation of yolk protein in the ovary and egg production was monitored. Humoral activity against the Gram‐positive bacterium Micrococcus luteus was induced by LPS injection in a dose‐responsive manner. LPS treatment also caused a concomitant significant reduction in the accumulation of protein in ovaries 24 h after injection and in the production of eggs during the same gonotrophic cycle. Unlike immune stimulation, reduction in reproductive fitness was not dose responsive. Oral administration of LPS also significantly reduced ovarian protein content although we could not detect the presence of anti‐M. luteus activity in the gut tissue by using an inhibition zone assay. These findings indicate that immune stimulation imposed reproductive fitness costs on mosquitoes.

Oral administration of lipopolysaccharides synergically enhances liver injury caused by chronic ethanol feeding in rats — A new animal model of alcoholic hepatitis

Oral administration of lipopolysaccharides synergically enhances liver injury caused by chronic ethanol feeding in rats — A new animal model of alcoholic hepatitis

Oral administration of lipopolysaccharides synergically enhances liver injury caused by chronic ethanol feeding in rats — A new animal model of alcoholic hepatitis

Oral administration of lipopolysaccharides synergically enhances liver injury caused by chronic ethanol feeding in rats — A new animal model of alcoholic hepatitis

Requirement of IL-5 for induction of autoimmune hemolytic anemia in anti-red blood cell autoantibody transgenic mice.

IL-5, IL-10 and lipopolysaccharide (LPS) are known to activate B-1 cells in vivo in normal mice and anti-red blood cell autoantibody transgenic mice (HL mice). To assess the exact role of IL-5 in proliferation and activation of peritoneal B-1 cells, we analyzed IL-5 receptor alpha chain-deficient HL (IL-5Ralpha-/- x HL) mice generated by the cross between IL-5Ralpha-/- and HL mice. In IL-5Ralpha-/- x HL mice, Ig-producing B-1 cells in the peritoneal cavity were negligible, although the total number of B-1 cells in the peritoneal cavity were as many as 30% of that in HL mice. Moreover, LPS- or IL-10-induced differentiation of B-1 cells into antibody-producing cells was severely impaired in IL-5Ralpha-/- x HL mice. We also used in vivo 5-bromo-2'-deoxyuridine labeling to estimate the proliferation of B-1 cells in IL-5Ralpha-/- mice. The absence of IL-5Ralpha did not affect spontaneous proliferation of peritoneal B-1 cells. However, induced proliferation of peritoreal B-1 cells by oral administration of LPS was markedly impaired in IL-5Ralpha-/- mice. These results suggest that IL-5 is required for activation-associated proliferation of B-1 cells but not for their spontaneous proliferation and support the idea that IL-5 plays an important role on the induction of autoantibody production from B-1 cells.

Suppression of experimental autoimmune encephalomyelitis by oral administration of myelin basic protein: III. Synergistic effect of lipopolysaccharide

Oral administration of myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis (EAE) in Lewis rats immunized with MBP in Freund's adjuvant. The immunomodulator bacterial lipopolysaccharide (LPS) when given orally in conjunction with MBP enhances the protective effects of MBP feeding in EAE. This synergy was achieved only following oral administration of LPS but not following subcutaneous injection. In contrast, subcutaneous administration of LPS abrogated oral tolerance. A synergism between oral LPS and MBP was also demonstrated for antigen-specific suppression of delayed type hypersensitivity (DTH) responses. Antibody responses to MBP were suppressed by oral administration of MBP but not by MBP plus LPS. The lipid A moeity of LPS mimicked the effects of LPS on disease protection and DTH suppression. These data demonstrate that adjuvants can enhance the induction of antigen-specific oral tolerance for suppression of cell-mediated experimental autoimmune responses.